D-108 Innate-primed alternative signaling pathways enhance functional mucosal mobilization of memory-like NK cells in HIV/SIV infection

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Burgeoning evidence indicates a broader functional repertoire for NK cells beyond innate immunity including adaptive functions. Specifically, memory-like NK cells lacking the FcR γ-signaling chain (FcRΔg-NK cells) still require antibody to grant antigen-specificity, but are pre-sensitized for rapid mobilization against viral antigens. Interestingly, FcRΔg-NK cells require innate priming by CMV, but execute memory-like killing against HIV and SIV through poorly understood mechanisms.Sixty rhCMV−, rhCMV+, and chronically SIV-infected macaques were studied and compared to thirty naive and untreated HIV-infected humans. FcRΔg-NK cells were systemically distributed but, correlating with viral load, increased four-fold in CMV+ and HIV/SIV-subjects, including in the GI tract. Upregulated CD16 and α4β7 suggested memory-like priming is required for both antibody-dependent functions and mucosal homing. FcRΔg-NK cells exhibited two-fold more robust IFN-γ secretion and cytotoxicity in the presence of antibody, but reduced expression of Helios and Eomes—indicative of epigenetic modifications, and clustered independently from traditional NK cells in multidimensional t-SNE. The γ-chain adaptor, Syk was absent or dephosphorylated in FcRΔg-NK cells, but ζ-chain, phosphorylated by adaptor Zap70, was significantly upregulated, indicating use of the alternative ζ-chain/Zap70 pathway to achieve greater functional potency.Our work presents the first description of a combinatorial mechanism of innate-priming and alternative signaling to explain the memory-like phenomena of NK cells mobilized against HIV/SIV. Future studies harnessing memory-like NK cells could create exciting modalities for both vaccine and curative therapies.

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